The ?-secretase enzyme (BACE1) is a major current focus for clinical trials in Alzheimer's disease therapy, as BACE1 is the rate-limiting enzyme in APP processing and in the generation of A? and amyloid deposition. We have been interested in how BACE1 enzyme levels are regulated. We have made three unexpected observations. First, the trophic factor BDNF, which is capable of preventing neurodegeneration in mice and humans, increases the transcription of an immediate early gene called Narp. Recent published data indicates that only low levels of Narp are detected in Alzheimer's subjects, suggesting that BDNF and Narp levels are beneficial. Second, Narp binds to BACE1. Experiments are being undertaken to see if the binding of Narp to BACE1 sequesters or alters BACE1 enzymatic activity. Finally, we find that BACE1 enzyme levels in the brain are highly correlated with the expression of the p75 neurotrophin receptor. Many common risk factors for Alzheimer's disease, such as aging, inflammation and hypoxia induce BACE1 activity. The p75 receptor is similarly elevated after nerve injury, seizures and inflammation in the CNS. The p75 receptor is frequently expressed highly during aging in neuronal populations that degenerate in Alzheimer's disease and its expression may reflect an early sign of neurodegeneration. We hypothesize BACE1 levels and its activity is affected by the expression of Narp and p75, two proteins involved in trophic factor action. We intend to test this hypothesis by measuring the amyloidogenic processing of APP, as a function of p75, Narp and BACE1 levels. These studies will determine how the trophic activity and the p75 receptor play either a positive or a negative role after environmental conditions of stress, injury and inflammation. We hypothesize that induction of p75 after brain injury or seizures and the binding of Narp represent regulatory mechanisms associated with BACE1 activity.